We have gathered data that indicate Mendel's law of independent assortment of non-homologous chromosomes may be violated in two specific instances: inheritance of retinoblastoma in the human, and the DDK syndrome in the mouse. In both of these cases, the genotypic ratios observed among the progeny of individuals that are heterozygous at marker loci on two non- homologous chromosomes differ significantly from the ratios predicted by Mendel's second law. In heritable retinoblastoma, the offspring of males that are the founders of retinoblastoma pedigrees have more affected male children and fewer unaffected female children than predicted, (i.e., they transmit their Y-chromosome, together with the chromosome 13 carrying the mutant RB-1 gene, more frequently than expected and/or transmit their X- chromosome, together with the chromosome 13 carrying the wild-type RB-1 gene less frequently than expected). In the DDK syndrome, the offspring of one class of reciprocal F1 females backcrossed to DDK males fail to receive grandpaternally-derived combinations of markers on the X- chromosome and chromosome 11 with the expected frequency and receive grandmaternally-derived combinations with greater frequency than expected. There are some similarities between these two phenomena. In both: 1) a sex chromosome and an autosome are involved; 2) the particular chromosome combinations that appear with unexpected frequencies among the progeny are related by the grandparental origin of the alleles; and 3) sex-ratio distortion in favor of males is observed among the offspring. There are also dissimilarities between the two phenomena. In the case of retinoblastoma, the observed transmission ratio distortion for two non- homologous chromosomes appears among the offspring of males, while in the DDK syndrome, the distortion appears among the offspring of F1 females. In the offspring of the male retinoblastoma patients, the observed distortion is in favor of the grandpaternal/grandpaternal (and/or against the grandmaternal/grandmaternal) combination of the two chromosomes, but in the offspring of the F1 females in the DDK syndrome, the observed bias is against the grandpaternal/grandpaternal (and/or in favor of the grandmaternal/grandmaternal) combination of the two chromosomes.